Diallylamine

Endpoint summary

Description of key information

Repeat dose toxicity - oral (OECD 422):

The oral administration of Diallylamine to rats for a period of up to eight weeks (including two weeks pre-pairing, gestation and early lactation for females) at dose levels of 15, 30 and 75 mg/kg bw/day did not result in any toxicologically significant effects.

Episodes of increased salivation were reported in animals of either sex treated with 75 mg/kg bw/day from Day 9 (males) and Day 13 (females) onwards. An increase in overall water consumption was also observed for females treated with 75 and 30 mg/kg bw/day. Observations of this nature are commonly observed following the oral administration of an unpalatable test item formulation and in isolation are generally regarded as not an adverse effect of systemic toxicity. Initial reductions/losses in body weight gain were evident in animals of either sex treated with 75 mg/kg bw/day and in males treated with 30 mg/kg bw/day which was associated with reduced food consumption at 75 mg/kg bw/day, however subsequent recovery was evident in all animals and body weight gains which, in subsequent weeks for treated males were actually higher than control males. Due to the initial effect on body weight development in males treated with 75 mg/kg bw/day, overall body weight gains for this group was lower than controls. Based on the overall effect on body weight performance together with the clear evidence of recovery, these findings were deemed not to be of an adverse nature.

Although there were some statistically significant differences in treated animals from controls for the blood chemical parameters measured, in the absence of any related microscopic changes these differences were considered not to be of toxicological significance.

No treatment-related macroscopic abnormalities were evident in treated animals however microscopic examination revealed changes in the adrenal gland (hypertrophy of the zona glomerulosa) of animals of either sex treated with 75 and 15 mg/kg bw/day and in one female treated with 30 mg/kg bw/day. Zona glomerulosa hypertrophy in the adrenal gland is seen occasionally in toxicology studies and whilst the significance is not clear, it is linked to hydration and electrolyte balance and is therefore seen as an adaptive response. Due to the low incidence, lack of dose response and limited number of animals per group it is considered that, within the confines of this study the change may reflect a variation in background levels, particularly in lactating females and cannot be unequivocally related to the administration of the test item and not considered to be an adverse event.

Microscopic examination of the kidneys revealed increased hyaline droplets in males treated with 75 mg/kg bw/day. Kidney weights were also elevated in these males. Hyaline droplets can be directly linked to the accumulation of alpha 2u-globulin, which is unique to the male rat. This finding is not found in immature rats, female rats or humans and therefore is considered to be of no relevance to man. Therefore, a ‘No Observed Adverse Effect Level’ (NOAEL) for males can be established based on the observed effects excluding those related to alpha 2u-globulin nephropathy.

The oral administration of Diallylamine to rats by gavage, at dose levels of 15, 30 and 75 mg/kg bw/day, did not result in any significant toxicological effects. The ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was therefore considered to be 75 mg/kg bw/day for either sex.

Repeat dose toxicity - inhalation:

Male rats were exposed to 0, 25, 50, 100 or 200 ppm of diallylamine vapour for seven hours/day for 50 days in order to assess cardiac and other organ system toxicity.

Reported effects at 200 ppm: 30% mortality; elevated heart, liver, kidney and lung / w ratios; decreased bw gain; microscopically, heart lesions were found in 11 of 15 rats.

The No Observed Effect Level (NOEL) was considered to be 25 ppm based on the absence of any effects at this level. The No Observed Adverse Effect level (NOAEL) was considered to be in the range of 50 -100 ppm based on the absence of cardiac lesions at these levels, but there was an elevated heart to bodyweight ratio.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

75 mg/kg bw/day

Study duration:

subacute

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

400 mg/m³

Study duration:

subacute

Species:

rat

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Repeat dose toxicity - oral

Target organ toxicity (repeated exposure) means specific, target organ toxicity arising from a repeated exposure to a substance or mixture. All signficant health effects that can impair function, both reversible and irreversible, immediate and/or delayed are included.

The test item was administered by gavage to three groups, each of twelve male and twelve female Wistar Han™:RccHan™:WIST strain rats, for up to eight weeks (including a two week pre-pairing phase, pairing, gestation and early lactation for females), at dose levels of 15, 30 and 75 mg/kg bw/day. 

The oral administration of Diallylamine to rats by gavage, at dose levels of 15, 30 and 75 mg/kg bw/day, did not result in any significant toxicological effects. The ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was therefore considered to be 75 mg/kg bw/day for either sex.

The CLP guideline values (based on 28-day study) for Cateogry 2 STOT-RE classification are >30 to ≤300 mg/kg bw/day. Classification is applicable when significant toxic effects observed in a repeated-dose toxicity study conducted in experimental animals are seen to occur within this guidance range.

Due to the corrosive nature of the substance, repeated-dose toxicity testing at a higher concentration than 75 mg/kg be/day was not possible i.e. it is not possible to test the substance up to and over the CLP guideline range (300 mg/kg bw/day and above) for classification.

However, as testing at 75 mg/kg bw/day did not result in any signficant toxicolgoical effects, the substance is not classified for specific target organ toxicity-repeated exposure (by the oral route).

Repeat dose toxicity - inhalation

In rats exposed to 50 7-hour exposures at 200 ppm (0. 8 mg/l) adverse effects (mortalilty and microscopic heart leasions) were observed. These effects are seen within the CLP guideline range for significant toxic effects applicable to Cateogry 2 classificaiton.

However, a classification for STOT-SE 2 is not applied as the repeat inhalation data is not considered of suitable reliabilty to assign a classification due to limited details on the effects observed. There is no detailed information provided on the heart lesions obserbed at 200 ppm e.g. if true systemic toxicity effects or secondary/adaptive effects possibly caused by corrosivity (inflammation of heart muscle can be associated with upper respiratory tract issues).

The other effects seen at 200 ppm and lower doses, elevated organ/bw ratios, are not considered to be significant adverse effects considered to support classification for specific target organ toxicity.

Also, the guidance range values are based on 6 hour/day expousre (vapour) to rats and 28 or 90 day exposures, wherease the available study has rats exposed for 50 days for 7 hours.

It is therefore considered that the available repeat dose inhalation data is not sufficient for classification.